CN114573560A - Preparation method of Voranolan fumarate - Google Patents
Preparation method of Voranolan fumarate Download PDFInfo
- Publication number
- CN114573560A CN114573560A CN202210266987.6A CN202210266987A CN114573560A CN 114573560 A CN114573560 A CN 114573560A CN 202210266987 A CN202210266987 A CN 202210266987A CN 114573560 A CN114573560 A CN 114573560A
- Authority
- CN
- China
- Prior art keywords
- fumarate
- compound
- preparation
- formula
- organic solvent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 title claims abstract description 49
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 22
- 239000003960 organic solvent Substances 0.000 claims abstract description 14
- 239000011259 mixed solution Substances 0.000 claims abstract description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 38
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- 150000001875 compounds Chemical class 0.000 claims description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 229940125898 compound 5 Drugs 0.000 claims description 6
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 239000003638 chemical reducing agent Substances 0.000 claims description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical group [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- 229940125904 compound 1 Drugs 0.000 claims description 3
- 229940125782 compound 2 Drugs 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- 239000012279 sodium borohydride Substances 0.000 claims description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 3
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 2
- 229940011051 isopropyl acetate Drugs 0.000 claims description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical group [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims 1
- 229910052744 lithium Chemical group 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 239000011734 sodium Chemical group 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 14
- 239000001530 fumaric acid Substances 0.000 abstract description 13
- 239000002699 waste material Substances 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 230000007613 environmental effect Effects 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 19
- 238000003756 stirring Methods 0.000 description 15
- 229940050411 fumarate Drugs 0.000 description 14
- 239000007787 solid Substances 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 238000001914 filtration Methods 0.000 description 9
- 239000007864 aqueous solution Substances 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 229940126214 compound 3 Drugs 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000001744 Sodium fumarate Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- MSJMDZAOKORVFC-SEPHDYHBSA-L disodium fumarate Chemical compound [Na+].[Na+].[O-]C(=O)\C=C\C([O-])=O MSJMDZAOKORVFC-SEPHDYHBSA-L 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 229940005573 sodium fumarate Drugs 0.000 description 3
- 235000019294 sodium fumarate Nutrition 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- ROGSHYHKHPCCJW-WLHGVMLRSA-N (e)-but-2-enedioic acid;1-[5-(2-fluorophenyl)-1-pyridin-3-ylsulfonylpyrrol-3-yl]-n-methylmethanamine Chemical compound OC(=O)\C=C\C(O)=O.C=1C=CN=CC=1S(=O)(=O)N1C=C(CNC)C=C1C1=CC=CC=C1F ROGSHYHKHPCCJW-WLHGVMLRSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 210000004211 gastric acid Anatomy 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 1
- 239000001747 Potassium fumarate Substances 0.000 description 1
- 102100021904 Potassium-transporting ATPase alpha chain 1 Human genes 0.000 description 1
- 108010083204 Proton Pumps Proteins 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- PMUKAEUGVCXPDF-SEPHDYHBSA-L dilithium;(e)-but-2-enedioate Chemical compound [Li+].[Li+].[O-]C(=O)\C=C\C([O-])=O PMUKAEUGVCXPDF-SEPHDYHBSA-L 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- BLKXGOSKCMAKDP-TYYBGVCCSA-M lithium;(e)-4-hydroxy-4-oxobut-2-enoate Chemical compound [Li+].OC(=O)\C=C\C([O-])=O BLKXGOSKCMAKDP-TYYBGVCCSA-M 0.000 description 1
- CEAJFNBWKBTRQE-UHFFFAOYSA-N methanamine;methanol Chemical compound NC.OC CEAJFNBWKBTRQE-UHFFFAOYSA-N 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- SHPKCSFVQGSAJU-SEPHDYHBSA-L potassium fumarate Chemical compound [K+].[K+].[O-]C(=O)\C=C\C([O-])=O SHPKCSFVQGSAJU-SEPHDYHBSA-L 0.000 description 1
- 235000019295 potassium fumarate Nutrition 0.000 description 1
- QPMDWIOUHQWKHV-TYYBGVCCSA-M potassium;(e)-but-2-enedioate;hydron Chemical compound [H+].[K+].[O-]C(=O)\C=C\C([O-])=O QPMDWIOUHQWKHV-TYYBGVCCSA-M 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of vorexant fumarate, belonging to the field of drug synthesis, wherein the vorexant fumarate is obtained by reacting fumarate with vorexant in a mixed solution of an organic solvent and water, so that the yield and the product quality are improved; on the other hand, the organic solvent and the fumaric acid can be recycled, thereby reducing the generation of three wastes and lowering the production cost. The method has the advantages of easily available raw materials, simple operation, high reaction yield, high product purity, low environmental protection pressure, low cost and easy commercial production.
Description
Technical Field
The invention relates to the field of drug synthesis, in particular to a method for preparing high-purity Voranolan fumarate.
Technical Field
Voranolan fumarate, developed and marketed in 2015 by Wutian pharmacy, is used as a novel oral gastric acid resistant drug and is mainly used for treating gastric acid related diseases. The inhibition effect of the vorexant fumarate on a proton pump does not need to be activated by acid, the vorexant fumarate enters the stomach at a high concentration, the maximal inhibition effect can be generated by the first administration, and the vorexant fumarate can last for 24 hours. Simultaneously has good tolerance and safety, and the chemical name is as follows: 1- [5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl]-N-methylMethylamine fumarate, CAS No.: 1260141-27-2, formula: c17H16FN3O2S·C4H4O4Molecular weight: 461.46, the structural formula is as follows:
the preparation of vorexanol fumarate as reported in prior art patents ZL2006800407897, ZL2017109790714, CN2019101964702, CN2019108981855, CN2019112952573, CN2016107238128, ZL2015109897464, ZL2016108789185, ZL2015100285655 and CN2019108109325 was obtained by salifying vorexanol with fumaric acid:
in the preparation method, because the solubility of fumaric acid is poor, the fumaric acid has relatively good solubility only in solvents such as methanol, DMAC (dimethylacetamide), DMF (dimethyl formamide), and the like, a high-boiling solvent is used in the salt forming process, and a mixed solvent is used, so that the solvents are difficult to recover three wastes, the environmental protection pressure is high, the product quality is influenced, and the salt forming yield is about 75%.
Disclosure of Invention
The invention aims to provide a preparation method of Vonopalafenate fumarate, which has the advantages of easily obtained raw materials, concise process, economy, environmental protection, less three wastes, recycled solvent and reagent, safety, high purity, high stability and high yield, and can be used for industrial production, so as to overcome the defects in the prior art.
The technical scheme is as follows: the synthesis route of the preparation method of Voranolan fumarate provided by the invention is as follows:
and reacting the intermediate 5 and the compound 7 in a mixed solution of an organic solvent and water in a volume ratio of 1: 1-10 to obtain the high-purity vonola fumarate (compound 8).
In some embodiments, the organic solvent is selected from one of toluene, ethyl acetate, isopropyl acetate.
In some embodiments, compound 7 is selected from the group consisting of mono potassium fumarate, mono sodium fumarate, mono lithium fumarate, preferably mono sodium fumarate.
In some embodiments, the molar ratio of intermediate 5 to compound 7 is 1: 2.0 to 5.0, preferably 1: 2.0 to 3.0, more preferably 1: 2.0 to 2.3.
Intermediate 5 can be obtained by various preparation methods in the prior art, such as:
(1) reacting the compound 1 and the compound 2 in an organic solvent under the action of a catalyst to obtain an intermediate 3;
(2) reacting the intermediate 3 with methylamine to generate an intermediate 4;
(3) and reducing the intermediate 4 by a reducing agent to obtain an intermediate 5.
The catalyst in the step (1) is triethylamine, and the organic solvent is acetonitrile.
And (4) the reducing agent in the step (3) is sodium borohydride or potassium borohydride.
Has the beneficial effects that: the method adopts the fumarate to react with the Vonopalagen in the mixed solution of the organic solvent and the water to obtain the Vonopalagen fumarate, the fumaric acid is hardly soluble in the water, and the solubility of the fumarate in the water is good, so that the reaction is easier to carry out; in the salifying process, a small-polarity organic solvent immiscible with water and water are used as reaction solvents, the obtained Vonopalago fumarate product has poor solubility in the small-polarity organic solvent and is almost insoluble in water, so that the product is directly and completely separated out, the post-treatment operation is simple, impurities which do not form salt are extracted to an organic layer, and hydrophilic salifying impurities are dissolved in water, so that a high-quality and high-yield product is obtained, the highest yield of the existing process is about 75%, the yield of the invention is 94%, the product quality is good, the highest purity of HPLC reported in the current literature is 99.7%, and the HPLC purity of the product obtained by the method is stable to over 99.9%; on the other hand, the organic solvent is recovered by distillation operation, and the water phase is used for recovering fumaric acid by adjusting the pH value of the system, so that the utilization rate of the reagent is improved, the generation of three wastes is reduced, the production cost is reduced, and the method is suitable for industrial production.
Drawings
FIG. 1 is an HPLC chart of Compound 3 of example 1;
FIG. 2 is a H-NMR chart of Compound 3 in example 2;
FIG. 3 is an HPLC chart of Compound 8 obtained in example 3 using an aqueous solution of sodium fumarate;
FIG. 4 is a H-NMR chart of Compound 8 obtained in example 3 using an aqueous solution of sodium fumarate;
FIG. 5 is an HPLC chart of Compound 8 of example 4.
Detailed Description
The invention is further illustrated below, but not limited thereto.
Example 1: preparation of Compound 3
Adding 530.00g of acetonitrile, 200.00g of compound 1, 26.08g of DMAP and 160.80g of triethylamine into a 500ml reaction bottle in sequence, starting stirring, controlling the temperature to be 15-35 ℃, dropwise adding 283.00g of compound 2 and 100.00g of acetonitrile solution, finishing dropwise adding about 30min, and dissolving a system firstly and then separating out a dark solid in the dropwise adding process; adding 4.00g of activated carbon at the temperature of 15-35 ℃ and reacting for 1-3 h in a heat preservation way; filtering, adding the filtrate into 900.00g of water with the temperature of 5-15 ℃, stirring for 1-2H at the constant temperature, filtering, rinsing the filter cake with water, and drying at 50 ℃ to obtain 321.26g of off-white solid compound 3 with the HPLC purity of 99.94%, the yield of 92%, and the delta of 1H-NMR (400MHz and DMSO): 9.91(S, 1H), 8.82 to 8.83(m, 1H), 8.58(d, J ═ 2.0Hz, 1H), 8.15(d, J ═ 1.6Hz, 1H), 7.69 to 7.72(m, 1H), 7.44 to 7.49(m, 1H), 7.35 to 7.39(m, 1H), 7.15 to 7.18(m, 2H), 7.00 to 7.04(t, 1H), 6.68(d, J ═ 2.0Hz, 1H).
Example 2: preparation of Compound 5
Adding 450.00g of methylamine methanol solution, 423.00g of methanol and 200.00g of compound 3 into a reaction kettle in sequence at 10-20 ℃, and stirring for 1-2 hours at the constant temperature; adding 10.31g of sodium borohydride (1/4 is added in each hour) in batches at the temperature of between 15 ℃ below zero and 10 ℃ below zero, and stirring for 1 hour under the condition of heat preservation after the addition is finished; controlling the temperature to be-15-10 ℃, dropwise adding the reaction liquid into 1211.85g of 2N hydrochloric acid, wherein the PH of the system is 3-4 after dropwise adding; controlling the temperature to be 45 ℃, concentrating under reduced pressure until no fraction is obtained, adding 2000.00g of toluene, cooling to below 30 ℃, and dropwise adding 444.00g of 10% sodium hydroxide solution to adjust the pH of the system to 10-11; separating the solution to obtain a toluene solution of the compound 5, directly feeding the solution to the next step, and taking a small sample to obtain the quantitative yield of 100%.
Example 3: preparation of Compound 8
(ii) an aqueous solution of sodium fumarate
Adding 730g of water and 73g of fumaric acid into a 2L reaction bottle at the temperature of 50-60 ℃, stirring and dispersing, controlling the temperature to be 50-60 ℃, dropwise adding a solution of 25g of sodium hydroxide and 300g of water into the suspension of the fumaric acid, gradually dissolving the system clearly in the dropwise adding process, and keeping the temperature of the obtained aqueous solution of the compound 7 for later use.
And (2) at the temperature of 25-35 ℃, taking one half of the toluene solution of the compound 5 obtained in the previous step, putting the toluene solution into a 5L reaction bottle, dropwise adding the water solution of the compound 7 into the reaction bottle, separating out white solid in the system in the dropwise adding process, preserving heat, stirring for 2-4H after dropwise adding is finished, filtering, drying a filter cake at the temperature of 50 ℃ to obtain 131.32g of white solid, wherein the HPLC purity is 99.96%, the yield is 94%, and the 1H-NMR (400MHz, DMSO) delta: 8.82 ~ 8.83(d, J ═ 2.8Hz, 1H), 8.56(d, J ═ 0.8Hz, 1H), 7.89 ~ 7.90(d, J ═ 5.6Hz, 1H), 7.83(S, 1H), 7.51 ~ 7.57(m, 2H), 7.21 ~ 7.23(t, 1H), 7.10 ~ 7.15(m, 2H), 6.46(S, 3H), 4.12(S, 2H), 2.72(S, 3H).
Mother liquor post-treatment scheme:
separating the mother liquor, concentrating the organic phase at 45 ℃ under reduced pressure, and collecting 980g of colorless transparent toluene with the recovery rate of 98%; adjusting the pH value of the system to be 3-4 by using concentrated hydrochloric acid in the water phase, separating out white solids in the system in the acid adjusting process, keeping the temperature, stirring for 1-2 h, filtering, and drying a filter cake at 50 ℃ to constant weight to obtain 32.55g of white fumaric acid solids, wherein the recovery rate is 85% and the purity is 99%.
② aqueous potassium fumarate solution
Adding 360g of water and 36.5g of fumaric acid into a 1L reaction bottle at the temperature of 50-60 ℃, stirring and dispersing, controlling the temperature to be 50-60 ℃, dropwise adding a solution of 17.5g of potassium hydroxide and 150g of water into the suspension of the fumaric acid, gradually dissolving the system in the dropwise adding process, and keeping the temperature of the obtained aqueous solution of the compound 9 for later use.
And (2) at 25-35 ℃, taking one fourth of the toluene solution of the compound 5 obtained in the example 2, placing the one fourth of the toluene solution into a 3L reaction bottle, dropwise adding the water solution of the compound 9 into the reaction bottle, separating out white solid in the dropwise adding process, stirring for 2-4 h at the constant temperature after dropwise adding, filtering, and drying a filter cake at 50 ℃ to obtain 65g of white solid with the yield of 93%.
③ lithium fumarate aqueous solution:
adding 360g of water and 36.5g of fumaric acid into a 1L reaction bottle at 50-60 ℃, stirring and dispersing, controlling the temperature to be 50-60 ℃, dropwise adding a solution of 7.5g of lithium hydroxide and 150g of water into the suspension of the fumaric acid, gradually dissolving the system in the dropwise adding process, and keeping the temperature of the obtained aqueous solution of the compound 10 for later use.
And (2) at 25-35 ℃, taking the remaining one fourth of the toluene solution of the compound 5 obtained in the example 2, putting the remaining one fourth of the toluene solution into a 3L reaction bottle, dropwise adding the aqueous solution of the compound 10 into the reaction bottle, separating out white solids in the dropwise adding process, preserving heat, stirring for 2-4 h after dropwise adding, filtering, and drying a filter cake at 50 ℃ to obtain 65.7g of white solids, wherein the yield is 94%.
Comparative example 4: compound 8 was prepared according to the method of Japanese Wutian patent CN104211618A
Taking the toluene solution obtained in the example 2, concentrating under reduced pressure to obtain 104.05g of light yellow oily matter, adding 200.0g of ethyl acetate and 600ml of DMAC, stirring and dissolving, dropwise adding 300ml of ethyl acetate at 30-45 ℃, cooling to 20-30 ℃ after dropwise adding, keeping the temperature and stirring for 1-2 h, filtering to obtain white solid, rinsing once with 100ml of ethyl acetate to obtain 123.0g of white solid, adding into a mixed solution of 600ml of methanol and 600ml of water at 65-75 ℃, stirring for 5min to completely dissolve, filtering, cooling the filtrate to 0-10 ℃, keeping the temperature and stirring for 1-2 h, filtering, rinsing the filter cake once with a mixed solution of 50ml of methanol and 50ml of water, drying at 50 ℃ to constant weight to obtain 100.58g of white solid, wherein the yield is 72%, and the purity is 98.13%.
And (3) comparison of a salifying system:
| reaction system | HPLC(％) | Yield (%) | Toluene recovery (%) |
| DMAC-EA | 98.13％ | 72％ | Recovery of special equipment |
| Toluene-monosodium fumarate | 99.96％ | 94％ | 98％ |
Claims (8)
1. A preparation method of Voranolan fumarate is characterized by comprising the following steps:
reacting the intermediate shown as the formula 5 with the intermediate shown as the formula 7 in a mixed solution of an organic solvent and water in a volume ratio of 1: 1-10 to obtain Voranolan fumarate shown as the formula 8;
wherein R is potassium, sodium or lithium.
2. The process of claim 1, wherein compound 7 is monosodium fumarate.
3. The method according to claim 1, wherein the molar ratio of the intermediate represented by the formula 5 to the intermediate represented by the formula 7 is 1: 2.0-5.0.
4. The preparation method according to claim 3, wherein the molar ratio of the intermediate shown as the formula 5 to the intermediate shown as the formula 7 is 1: 2.0-3.0.
5. The preparation method according to claim 3, wherein the molar ratio of the intermediate shown as the formula 5 to the intermediate shown as the formula 7 is 1: 2.0-2.3.
6. The method according to claim 1, wherein the organic solvent is selected from toluene, ethyl acetate, and isopropyl acetate.
7. The process according to claim 1, wherein Compound 5 is prepared by
8. The preparation method according to claim 7, characterized in that the preparation method comprises the following specific steps:
(1) reacting the compound 1 and the compound 2 in an organic solvent under the action of a catalyst to obtain an intermediate 3; the catalyst is triethylamine, and the organic solvent is acetonitrile;
(2) reacting the intermediate 3 with methylamine to generate an intermediate 4;
(3) and reducing the intermediate 4 by a reducing agent to obtain an intermediate 5, wherein the reducing agent is sodium borohydride or potassium borohydride.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210266987.6A CN114573560B (en) | 2022-03-17 | 2022-03-17 | Preparation method of voronoi fumarate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210266987.6A CN114573560B (en) | 2022-03-17 | 2022-03-17 | Preparation method of voronoi fumarate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114573560A true CN114573560A (en) | 2022-06-03 |
| CN114573560B CN114573560B (en) | 2024-02-06 |
Family
ID=81779666
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210266987.6A Active CN114573560B (en) | 2022-03-17 | 2022-03-17 | Preparation method of voronoi fumarate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114573560B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115232106A (en) * | 2022-07-29 | 2022-10-25 | 南京唯创远医药科技有限公司 | Preparation method of vorexan fumarate impurity |
| CN115232107A (en) * | 2022-07-29 | 2022-10-25 | 南京唯创远医药科技有限公司 | Preparation method of high-purity Voranolan fumarate |
| CN116003383A (en) * | 2022-12-30 | 2023-04-25 | 山东铂源药业股份有限公司 | Preparation method of voronoi |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104860926A (en) * | 2015-06-10 | 2015-08-26 | 浙江诚意药业股份有限公司 | Preparation method of vonoprazan fumarate |
| CN107011325A (en) * | 2016-01-27 | 2017-08-04 | 广东赛烽医药科技有限公司 | A kind of preparation method of Vonoprazan fumarate |
| CN111527067A (en) * | 2017-12-27 | 2020-08-11 | 日本化学药品株式会社 | Process for producing 1- [ 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl ] -N-methylmethanemethanemetic acid salt |
-
2022
- 2022-03-17 CN CN202210266987.6A patent/CN114573560B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104860926A (en) * | 2015-06-10 | 2015-08-26 | 浙江诚意药业股份有限公司 | Preparation method of vonoprazan fumarate |
| CN107011325A (en) * | 2016-01-27 | 2017-08-04 | 广东赛烽医药科技有限公司 | A kind of preparation method of Vonoprazan fumarate |
| CN111527067A (en) * | 2017-12-27 | 2020-08-11 | 日本化学药品株式会社 | Process for producing 1- [ 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl ] -N-methylmethanemethanemetic acid salt |
Non-Patent Citations (2)
| Title |
|---|
| CAROL A. ROA ENGEL 等: "Solubility of Fumaric Acid and Its Monosodium Salt", 《INDUSTRIAL & ENGINEERING CHEMISTRY RESEARCH》 * |
| 国家药典委员会: "《各国药用辅料标准对比手册》", 31 March 2016 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115232106A (en) * | 2022-07-29 | 2022-10-25 | 南京唯创远医药科技有限公司 | Preparation method of vorexan fumarate impurity |
| CN115232107A (en) * | 2022-07-29 | 2022-10-25 | 南京唯创远医药科技有限公司 | Preparation method of high-purity Voranolan fumarate |
| CN116003383A (en) * | 2022-12-30 | 2023-04-25 | 山东铂源药业股份有限公司 | Preparation method of voronoi |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114573560B (en) | 2024-02-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN114573560A (en) | Preparation method of Voranolan fumarate | |
| CN111704555B (en) | Method for synthesizing 4-methoxy-2-nitroaniline by adopting continuous flow reactor | |
| CN113956312A (en) | Preparation method of mopilavir | |
| CN110590635A (en) | Preparation method of levetiracetam and intermediate thereof | |
| CN110790721B (en) | Synthetic method of ceftazidime side chain ethyl ester | |
| CN109503513B (en) | One-pot synthesis method of febuxostat intermediate | |
| CN113651798A (en) | Preparation method of Voranolan fumarate | |
| CN113461508B (en) | Preparation method of alpha-ketophenylalanine calcium | |
| CN109574992B (en) | Preparation method of fasudil hydrochloride | |
| CN113880846A (en) | Preparation method of 7-iodopyrrolo [2,1-F ] [1,2,4] triazine-4-amine | |
| CN111233835A (en) | Preparation and purification method of 5- (2-fluorophenyl) -1- (pyridine-3-ylsulfonyl) -1H-pyrrole-3-formaldehyde | |
| CN111635325A (en) | Method for preparing metoprolol succinate | |
| CN111303045A (en) | Production process of 2-ethoxy-4, 6-difluoropyrimidine | |
| CN111747926A (en) | Improved method for synthesis process of free hydroxypiperone alkali | |
| CN113004281A (en) | Preparation method of entecavir intermediate | |
| CN110938036A (en) | Preparation method of 4-iodine-1H-imidazole | |
| CN114835689B (en) | Solvent-free method for preparing irbesartan | |
| CN114369073B (en) | Method for preparing high-purity hydrochlorothiazide | |
| CN115322239B (en) | Method for recovering diketone from mandipropamid carbon loss ester mother liquor | |
| CN114634455B (en) | Method for synthesizing 5-bromo-1H-3-amino-1, 2, 4-triazole | |
| CN115477653B (en) | Preparation method of trehalfline key intermediate and trehalfline | |
| CN110643659B (en) | Method for synthesizing decitabine | |
| WO2012048451A1 (en) | Preparation process of (6r)-tetrahydrobiopterin hydrochloride | |
| CN114394941A (en) | Preparation method of 2, 4-diamino-6-chloropyrimidine | |
| CN117327021A (en) | Method for removing sticky impurities in hexahydropyridazine synthesis |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |